The mesolimbic dopamine (DA) system has been primarily implicated in the effects of psychostimulants. While this pathway and DA signaling are the focus of most research in this area, it is also clear that norepinephrine (NE) plays an important role in modulating the neurochemical and behavioral responses to in animal models. The enzyme dopamine beta-hydroxylase (DBH) converts DA to NE in noradrenegic cells, thus controlling the abundance of both NE and DA in the brain. Genetic and pharmacological data in humans support an important role for DBH in modulating psychostimulant-related behaviors. First, a common polymorphism in the human Dbh gene is a critical determinant of DBH enzymatic activity and appears to influence behavioral and cognitive responses to cocaine. Second, the DBH inhibitor disulfiram (Antabuse) has shown striking promise as a treatment for cocaine dependence. The objective of this proposal is to determine the influence of DBH activity on catecholamine neurochemistry and cocaine-related behaviors, including sensitization, reward, aversion, and relapse, which will be accomplished by using a combination of genetics (Dbh knockout mice), and pharmacology (DBH inhibitors). Completion of the aims in this proposal will contribute to our understanding of how the interaction between noradrenergic and dopaminergic systems influences drug addiction and the mechanism of disulfiram-induced cocaine abstinence, and will suggest novel treatments for psychostimulant dependence.